Mitochondrial oxidative stress and respiratory chain dysfunction account for liver toxicity during amiodarone but not dronedarone administration

Gaetano Serviddio, Francesco Bellanti, Anna Maria Giudetti, Gabriele Vincenzo Gnoni, Nazzareno Capitanio, Rosanna Tamborra, Antonino Davide Romano, Maurizio Quinto, Maria Blonda, Gianluigi Vendemiale, Emanuele Altomare

Research output: Contribution to journalArticle

Abstract

The role played by oxidative stress in amiodarone-induced mitochondrial toxicity is debated. Dronedarone shows pharmacological properties similar to those of amiodarone but several differences in terms of toxicity. In this study, we analyzed the effects of the two drugs on liver mitochondrial function by administering an equivalent human dose to a rat model. Amiodarone increased mitochondrial H 2O 2 synthesis, which in turn induced cardiolipin peroxidation. Moreover, amiodarone inhibited Complex I activity and uncoupled oxidative phosphorylation, leading to a reduction in the hepatic ATP content. We also observed a modification of membrane phospholipid composition after amiodarone administration. N-acetylcysteine completely prevented such effects. Although dronedarone shares with amiodarone the capacity to induce uncoupling of oxidative phosphorylation, it did not show any of the oxidative effects and did not impair mitochondrial bioenergetics. Our data provide important insights into the mechanism of mitochondrial toxicity induced by amiodarone. These results may greatly influence the clinical application and toxicity management of these two antiarrhythmic drugs.

Original languageEnglish
Pages (from-to)2234-2242
Number of pages9
JournalFree Radical Biology and Medicine
Volume51
Issue number12
DOIs
Publication statusPublished - Dec 15 2011

Keywords

  • Antioxidants
  • Drugs
  • Free radicals
  • Hepatotoxicity
  • Lipid peroxidation
  • Mitochondrial dysfunction

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

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  • Cite this

    Serviddio, G., Bellanti, F., Giudetti, A. M., Gnoni, G. V., Capitanio, N., Tamborra, R., Romano, A. D., Quinto, M., Blonda, M., Vendemiale, G., & Altomare, E. (2011). Mitochondrial oxidative stress and respiratory chain dysfunction account for liver toxicity during amiodarone but not dronedarone administration. Free Radical Biology and Medicine, 51(12), 2234-2242. https://doi.org/10.1016/j.freeradbiomed.2011.09.004